ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5663A>G (p.Lys1888Arg) (rs80358791)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131719 SCV000186758 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113457 SCV000146661 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Color RCV000131719 SCV000903262 likely benign Hereditary cancer-predisposing syndrome 2016-04-29 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735571 SCV000863709 uncertain significance Breast and/or ovarian cancer 2016-05-18 no assertion criteria provided clinical testing
GeneDx RCV000216952 SCV000278864 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5663A>G at the cDNA level, p.Lys1888Arg (K1888R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 5891A>G. This variant was observed in an individual with ovarian cancer (Smirnova 2007). BRCA2 Lys1888Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys1888Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779946 SCV000916891 uncertain significance not specified 2017-09-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5663A>G (p.Lys1888Arg) variant involves the alteration of a non-conserved nucleotide that leads to a missense change. Since lysine and arginine have similar physicochemical properties, it can be considered a conservative amino acid replacement. The lysine residue is also weakly conserved across species and arginine is found in multiple mammalian species at this position, suggesting that this alteration might not be detrimental to protein function. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been confirmed by published functional studies. This variant was found in 2/120712 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). One individual listed in the BIC database carried the variant along with a co-occurring pathogenic BRCA1 mutation (c.2934T>G, p.Tyr978Ter), suggesting that the variant of interest was not the primary cause of disease. The variant was reported in an affected individual in the literature without strong evidence for causality (Smirnova 2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000044713 SCV000072726 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1888 of the BRCA2 protein (p.Lys1888Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs80358791, ExAC 0.003%). This variant has been reported in an individual affected with ovarian cancer (PMID: 18256760). ClinVar contains an entry for this variant (Variation ID: 51903). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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